Pharmacotherapy of Cardiovascular Diseases Myocardial Infarction, Hypertension, Congestive Heart Failure, Heperlipidemia

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  • Slide 1
  • Pharmacotherapy of Cardiovascular Diseases Myocardial Infarction, Hypertension, Congestive Heart Failure, Heperlipidemia.
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  • Novel mechanism for cell fate regulation in human vascular and blood cells Fig: Cardiovascular disease and cell fate of the human vascular and blood cells.
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  • Figure 2: Cell fate control in the human vascular and blood cells.
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  • Elucidations of the regulatory and pathophysiological molecular mechanisms of control systems for cell fate in the human cells yield information regarding the drug action, metabolism and the target of therapeutic drug discovery. The cell surface GPCR (G-protein-coupled receptor (IP)) and nuclear receptor PPAR (peroxisome proliferator-activated receptor (delta)), a regulator of energy metabolism and a key target for obesity and adipogenesis, have important roles in regulation of cell fate in a cooperative and/or competitive manner. The new methods for regulation of human vascular and blood cells via related signaling pathways.
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  • Myocardial Infarction Drugs used in Anginal Pain: (1) Organic Nitrates *Glyceryl Trinitrates (GTN) / Nitroglycerin. (2) Calcium Channel Blockers- * Verapamil, * Nifedipine. (3) Beta-adrenoceptor Blockers- * Atenolol, * Propanolol. (4) Dipyridamol.
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  • M/A of Organic Nitrates: Organic Nitrates act solely by relaxing smooth muscle of blood vessels by the following way. (1) Denitration of organic nitrates. (Organic Nitrates- Inorganic Nitrates). (2) Inorganic nitrates are converted to NO (Such as EDRF). (3) Activation of Guanylyl Cyclase (GC) by NO. (4) Increase formation of cGMP. (5) cGMP reduces intracellular Ca +++ conc. (6) Relaxation of vasular smooth muscle, Increase coronary flow. Generalized vasodilation: Decrease Blood Pressure. (7) Improve Myocardial perfusion. Reduce myocardial oxygen demand.
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  • History of Nitroglycerin Nitroglycerin, which was originally synthesized by Ascanio Sobrero, was used by Alfred Nobel to manufacture dynamite. It was in Nobel's dynamite factories in the late 1860s that the antianginal effect of nitroglycerin was discovered. Two interesting observations were made. First, factory workers on Monday mornings often complained of headaches that disappeared over the weekends. Second, factory workers suffering from angina pectoris or heart failure often experienced relief from chest pain during the work week, but which recurred on weekends. Both effects were attributed to the vasodilator action of nitroglycerin, which quickly became apparent to the physicians and physiologists in local communities. In the late 1970s and early 1980s, the vasodilator effect of nitroglycerin was discovered to be caused by nitric oxide (NO), which was apparently generated from nitroglycerin in vascular smooth muscle, Nitric Oxide as a Signaling Molecule in the Cardiovascular System.
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  • Molecular Mechanism of nitroglycerin Nitroglycerin (GTN), often used in conditions of cardiovascular ischaemia, acts through the liberation of nitric oxide (NO) and the local concentration of NO in the tissue is responsible for any biological effect. However, little is known about the way in which the concentration of NO from GTN and other NO-donors is influenced by low oxygen tension in the target tissues. The biological effect of NO is dependent of the concentration at the site of action. under hypoxic conditions the endogenous, L-arginine dependent NO synthesis may be impaired. Even the generation of exogenous' NO from different NO-donors is likely to be sensitive to alterations in tissue PO2. Nitrite (NO2) is a metabolite of organic nitrates. Therefore, the increase of NO from GTN during hypoxia might be due to increased indirect metabolism of GTN through the conversion of NO2 to NO. To evaluate this possibility we infused increasing concentrations of inorganic NO2 and NO3 in buffer-perfused lungs during hypoxic conditions. The mechanism for increase of GTN-derived NO during hypoxia was via increased conversion of NO2 to NO. The mitochondrial aldehyde dehydrogenase (ALDH2, mtALDH) was recently found to catalyze the reduction of nitroglycerin (glyceryl trinitrate [GTN]) to generate nitrite and 1,2-glyceryl dinitrate. The nitrite generated within the mitochondria is metabolized further to generate nitric oxide (NO)-based bioactivity, by reduction to NO and/or by conversion to S-nitrosothiol, as revealed by a series of biochemical, pharmacologic, and genetic studies.
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  • Nitric oxide (NO), a molecule produced by many cells in the body, and has several important actions. In the cardiovascular system, NO is primarily produced by vascular endothelial cells. This endothelial- derived NO has several important functions including relaxing vascular smooth muscle (vasodilation), inhibiting platelet aggregation (anti-thrombotic), and inhibiting leukocyte-endothelial interactions (anti-inflammatory). These actions involve NO- stimulated formation of cGMP. Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues. These drugs act directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelial-independent vasodilators.
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  • There are two basic types of nitrodilators: those that release NO spontaneously (e.g., sodium nitroprusside) and organic nitrates that require an enzymatic process to form NO. Organic nitrates do not directly release NO, however, their nitrate groups interact with enzymes and intracellular sulfhydryl groups that reduce the nitrate groups to NO or to S-nitrosothiol, which then is reduced to NO. Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation. NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.
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  • Organic nitrates can dilate both arteries and veins, venous dilation predominates when these drugs are given at normal therapeutic doses. Venous dilation reduces venous pressure and decreases ventricular preload. This reduces ventricular wall stress and oxygen demand by the heart, thereby enhancing the oxygen supply/demand ratio. A reduction in preload (reduced diastolic wall stress) also helps to improve subendocardial blood flow, which is often compromised in coronary artery disease. Mild coronary dilation or reversal of coronary vasospasm will further enhance the oxygen supply/demand ratio and diminish the anginal pain. Coronary dilation occurs primarily in the large epicardial vessels, which diminishes the likelihood of coronary vascular steal. Systemic arterial dilation reduces afterload, which can enhance cardiac output while at the same time reducing ventricular wall stress and oxygen demand. At high concentrations, excessive systemic vasodilation may lead to hypotension and a baroreceptor reflex that produces tachycardia. When this occurs, the beneficial effects on the oxygen supply/demand ratio are partially offset. Furthermore, tachycardia, by reducing the duration of diastole, decreases the time available for coronary perfusion, most of which occurs during diastole.
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  • Calcium Channel Blockers Ca ++ is required for: (1) Cardiac contraction, (2) Smooth muscle contraction, (3) Propagation of cardiac impulse. Main Calcium Antagonists are- Nifedipine ( relative smooth muscle selective), Amlodipine (), Verapamil (relatively cardioselective), Diltiazem (intermediate in action).
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  • M/A of Calcium Channel Blockers Ca ++ channel blockers -> Binds with voltage dependent Ca ++ channel in depolarized membrane. (The drugs act from inner side of the membrane). Decrease in transmembrane Ca ++ current -> Smooth muscle: relaxation Heart: negative ionotropic action.
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  • Flow chart: Ca ++ channel Ca ++ channel Blockers (-) Ca ++ Calmodulin Ca ++ calmodulin complex. Active MLCK-------------- Myosin- LC Kinase (MLCK) Myosin light chain (MLC) --------- Myosin LC-PO 4 ------------- MLC Actin Contraction Relaxation
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  • Molecular mechanism of Calcium Channel blockers L-type channels control voltage-dependent Ca2+ influx into cardiac and vascular smooth muscle, channel blockers inhibit depolarization-induced Ca2+ entry into muscle cells in the cardiovascular system. This causes a decrease in blood pressure, reduced cardiac contractility (and hence oxygen consumption) and antiarrhythmic effects. Therefore these drugs are used clinically to treat hypertension, myocardial ischemia and cardiac arrhythmias. Ca2+ channel block by calcium antagonists: Like other voltage-gated cation channels, Ca2+ channels exist in at least three states. A resting state stabilized at negative potentials (such as the resting potentials of most electrically excitable cells) which is a closed state from which the channel can open. The open state is induced by depolarization. Channels do not stay open indefinitely because they are turned off during prologend depolarization by transition into an inactivated state. Once the cell repolarizes inactivated channels return to the resting state and are now again available for opening. Ca2+ channel blockers inhibit Ca2+ flux mainly by allosterically stabil